Haltom Amanda R, Hassen Wafa E, Hensel Janine, Kim Jiha, Sugimoto Hikaru, Li Bingrui, McAndrews Kathleen M, Conner Meagan R, Kirtley Michelle L, Luo Xin, Xie Bingqing, Volpert Olga V, Olalekan Susan, Maltsev Natalia, Basu Anindita, LeBleu Valerie S, Kalluri Raghu
Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX.
Department of Bioengineering, Rice University, Houston, TX.
Extracell Vesicle. 2022 Dec;1. doi: 10.1016/j.vesic.2022.100014. Epub 2022 Oct 27.
Dysregulated Myc signaling is a key oncogenic pathway in glioblastoma multiforme (GBM). Yet, effective therapeutic targeting of Myc continues to be challenging. Here, we demonstrate that exosomes generated from human bone marrow mesenchymal stem cells (MSCs) engineered to encapsulate siRNAs targeting Myc (iExo-Myc) localize to orthotopic GBM tumors in mice. Treatment of late stage GBM tumors with iExo-Myc inhibits proliferation and angiogenesis, suppresses tumor growth, and extends survival. Transcriptional profiling of tumors reveals that the mesenchymal transition and estrogen receptor signaling pathways are impacted by Myc inhibition. Single nuclei RNA sequencing (snRNA-seq) shows that iExo-Myc treatment induces transcriptional repression of multiple growth factor and interleukin signaling pathways, triggering a mesenchymal to proneural transition and shifting the cellular landscape of the tumor. These data confirm that Myc is an effective anti-glioma target and that iExo-Myc offers a feasible, readily translational strategy to inhibit challenging oncogene targets for the treatment of brain tumors.
失调的Myc信号通路是多形性胶质母细胞瘤（GBM）中的关键致癌途径。然而，对Myc进行有效的治疗靶向仍然具有挑战性。在此，我们证明，由工程化封装靶向Myc的小干扰RNA（siRNA）的人骨髓间充质干细胞（MSC）产生的外泌体（iExo-Myc）定位于小鼠原位GBM肿瘤。用iExo-Myc治疗晚期GBM肿瘤可抑制增殖和血管生成，抑制肿瘤生长，并延长生存期。肿瘤的转录谱分析表明，间充质转变和雌激素受体信号通路受Myc抑制的影响。单核RNA测序（snRNA-seq）显示，iExo-Myc治疗可诱导多种生长因子和白细胞介素信号通路的转录抑制，引发间充质向神经前体细胞的转变，并改变肿瘤的细胞格局。这些数据证实，Myc是一个有效的抗胶质瘤靶点，iExo-Myc为抑制具有挑战性的致癌基因靶点以治疗脑肿瘤提供了一种可行的、易于转化的策略。
